#Mendelian Randomization Analysis: Social Isolation and Alzheimer's Disease By Dr. Shea Andrews, generated on 2018-09-08
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Social Isolation Day et al Nat Commu 2018: In up to 452,302 UK Biobank study participants, we perform genome-wide association study analyses for loneliness and identify 15 genomic loci (P < 5 × 10−8) for loneliness.
Late Onset Alzheimer’s disease Lambert et al 2013: The International Genomics of Alzheimer’s Project (IGAP) is a meta-analysis of 4 previously published GWAS datasets: the European Alzheimer’s Disease Imitative (EADI), the Alzheimer Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), and Genetic and Environmental Risk in AD (GERAD) and includes a sample of 17,008 LOAD cases and 37,154 cognitively normal elder controls. Participants in IGAP were of European ancestry, the average age was 71 and 58.4% of participants were women.
Alzheimer’s Age of Onset Surivial Huang et al 2017: A GWAS of age of onset in LOAD was conducted in 14,406 AD case samples and 25,849 control samples from the IGAP using Cox proportional hazard regressions. Participants were of European ancestry, in cases the the average AAO was 74.8 and 61.7% were women, in controls the average AAE was 79.0 and 59.6% were women.
CSF Ab42, tau & ptau Deming et al 2017: A GWAS of CSF AB42, ptau and tau levels (pg/mL) was conducted in 3,146 participants. Participants were of Eurpean ancestry.
Hippocampal Volume Hibar et al 2017: A GWAS of hippocampal volume perfomed in 26,814 (ENIGMA and CHARGE consortiums) individules of European Ancestry discovered 9 independent loci.
LD Clumping: For standard two sample MR it is important to ensure that the instruments for the exposure are independent. LD clumping can be performed using the data_clump function from the TwoSampleMR package, which uses EUR samples from the 1000 genomes project to estimate LD between SNPs and amonst SNPs that have and LD above a given threshold, only the SNP with the lowest p-value will be retained.
Proxy SNPs: SNPs associated with Social Isolation were extracted from the GWAS of LOAD, AAOS, AB42, ptau and tau. Where SNPs were not available in the outcome GWAS, the EUR thousand genomes was queried to identified potential proxy SNPs that are in linkage disequilibrium (r2 > 0.8) of the missing SNP.
Of the the 135 SNPs associated with Social Isolation, 124 were available in the LOAD GWAS (Table 2).
Table 2: SNPS associated with Social Isolation avalible in LOAD GWASOf the the 135 SNPs associated with Social Isolation, 133 were available in the AAOS GWAS (Table 3).
Table 3: SNPS associated withOf the the 135 SNPs associated with Social Isolation, 100 were available in the CSF AB42 GWAS (Table 4).
Table 4: SNPS associated with Social Isolation avalible in ab42 GWASOf the the 135 SNPs associated with Social Isolation, 105 were available in the CSF Ptau GWAS (Table 5).
Table 5: SNPS associated with Social Isolation avalible in Ptau GWASOf the the 135 SNPs associated with Social Isolation, 100 were available in the CSF Tau GWAS (Table 6).
Table 6: SNPS associated with Social Isolation avalible in tau GWASOf the the 135 SNPs associated with Social Isolation, 129 were available in the Hippocampal volume (Table 7).
Table 7: SNPS associated with Social Isolation avalible in Hippocampal volume GWASHarmonize the exposure and outcome datasets so that the effect of a SNP on the exposure and the effect of that SNP on the outcome correspond to the same allele. The harmonise_data function from the TwoSampleMR package can be used to perform the harmonization step, by default it try’s to infer the forward strand alleles using allele frequency information. EAF were not availbe in the IGAP summary statisitics, as such the allele frequencies reported in the AAOS anaylsis were used.
Pleiotropy was assesed using Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), that allows for the evlation of evaluation of horizontal pleiotropy in a standared MR model. MR-PRESSO performs a global test for detection of horizontal pleiotropy and correction of pleiotropy via outlier removal.
Social Isolation ~ LOAD: The MR-PRESSO global test for pleiotropy was significant (p = 0.0409). The following SNPs were removed due to pleiotropy: rs11605348, rs12364432
Social Isolation ~ AAOS: The MR-PRESSO global test for pleiotropy was non-significant.
Social Isolation ~ AB42: The MR-PRESSO global test for pleiotropy was non-significant.
Social Isolation ~ Ptau: The MR-PRESSO global test for pleiotropy was non-significant.
Social Isolation ~ Tau: The MR-PRESSO global test for pleiotropy was non-significant..
Social Isolation ~ hippocampal volume: The MR-PRESSO global test for pleiotropy was significant (p = 0.0177). The following SNPs were removed due to pleiotropy: No significant outliers
To obtain an overall estimate of causal effect, the SNP-exposure (Major Depressive Disorder) and SNP-outcome coefficients (Alzheimer’s disease and Alzheimer’s Age of Onset) were combined in 1) a random-effects meta-analysis using an inverse-variance weighted approach (IVW); 2) a Weighted Median approach; 3) and Egger Regression. IVW is equivalent to a weighted regression of the SNP-outcome coefficients on the SNP-exposure coefficients with the intercept constrained to zero. This method assumes that all variants are valid instrumental variables based on the Mendelian randomization assumptions. The causal estimate of the IVW analysis expresses the causal increase in the outcome (or log odds of the outcome for a binary outcome) per unit change in the exposure. Weighted median MR allows for 50% of the instrumental variables to be invalid. MR-Egger regression allows all the instrumental variables to be subject to direct effects (i.e. horizontal pleiotropy), with the intercept representing bias in the causal estimate due to pleiotropy and the slope representing the causal estimate.
Social Isolation
Social Isolation: 3907 SNPs (Table 1) were assoicated with were associated with Social Isolation at p < 5e-6. After LD clumping, 3772 of 3907 SNPs were removed.
Table 1: Independent SNPS associated with Social Isolation